Bone and Mineral Disorders
A previously externally MRC funded consortium managed by Dr Chris Esapa and lead by Professor Raj Thakker at the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, has established mouse models for human diseases such as osteoporosis, osteoarthritis, renal diseases, ectopic calcification and skeletal dysplasias.
These were identified using both phenotype-driven and gene-driven ENU mutagenesis approaches. In the phenotype-driven approach mice were investigated for radiographic anomalies using a Faxitron digital X-ray scanner, for alterations in bone mineral density using a PiXimus dual energy X-ray absorptiometer and for alterations in bone metabolites using plasma/serum biochemistry tests. The gene-driven approach involved high throughput screening of the ENU mutagenesis DNA archive for mutations in genes of interest.
In the phenotype-driven screen of 8,240 mutagenised mice, skeletal abnormalities were demonstrated in ~8% (i.e. 649) and inheritance testing was undertaken in >18% (i.e. 119) of these. To date autosomal dominant or recessive inheritance for abnormal phenotype was demonstrated in ~23% (i.e. 27) mice. These inherited phenotypes include: 4 models for low bone mineral density (BMD) and osteoporosis; 8 for skeletal dysplasias; 2 for craniofacial defects; 2 for kyphosis; 1 for renal failure and parathyroid disease; 5 for phosphate disorders and tumoural calcinosis; 4 for mineralisation defects including rickets, and 1 for hypercalciuric nephrolithiasis.
In the genotype-driven studies mutations in genes associated with osteoarthritis, which is a late onset phenotype, were screened for in the MRC Harwell 10,000 mutagensied DNA archive. The 10 genes investigated include: the growth and differentiation factor 5 (Gdf5); cartilage intermediate layer protein (Cilp); asporin (Aspn); sparc-related modular calcium binding protein 2 (Smoc2); type II iodothyronine deiodinase (Dio2); procollagen type IX, alpha 3 (Col9a3); progressive ankylosis (Ank); vitamin D 25-hydroxylase (Cyp2r1); fragilis-related osteoblast 1 (Frog1); and fat mass and obesity (Fto) gene. These have established 10 potential mutants for osteoarthritis, 3 for osteoporosis, 1 for hypercalciuric nephrolithiasis, and 1 for chondrocalcinosis. Thus a valuable resource of 42 (27 from phenotype-driven and 15 from gene-driven screens) mouse models for heritable skeletal disorders has been established, for future research into the genetic causation and treatments for bone disorders.
There is on-going work to exploit this resource that can be used in studies to bridge the paucity of knowledge concerning genetic pathways that contribute to bone mineralization and homeostasis particularly in relation to common conditions such as osteoarthritis.